PMID:9560273
| Citation |
Barrett, JF, Goldschmidt, RM, Lawrence, LE, Foleno, B, Chen, R, Demers, JP, Johnson, S, Kanojia, R, Fernandez, J, Bernstein, J, Licata, L, Donetz, A, Huang, S, Hlasta, DJ, Macielag, MJ, Ohemeng, K, Frechette, R, Frosco, MB, Klaubert, DH, Whiteley, JM, Wang, L and Hoch, JA (1998) Antibacterial agents that inhibit two-component signal transduction systems. Proc. Natl. Acad. Sci. U.S.A. 95:5317-22 |
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| Abstract |
A class of antibacterials has been discovered that inhibits the growth of Gram-positive pathogenic bacteria. RWJ-49815, a representative of a family of hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive antibacterial, inhibits the autophosphorylation of kinase A of the KinA::Spo0F two-component signal transduction system in vitro. Analogs of RWJ-49815 vary greatly in their ability to inhibit growth of bacteria and this ability correlates directly with their activity as kinase A inhibitors. Compared with the potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence in a laboratory passage experiment. Inhibition of the histidine protein kinase::response regulator two-component signal transduction pathways may present an opportunity to depress chromosomal resistance emergence by targeting multiple proteins with a single inhibitor in a single bacterium. Such inhibitors may represent a class of antibacterials that potentially may represent a breakthrough in antibacterial therapy. |
| Links | |
| Keywords |
Anti-Bacterial Agents/pharmacology; Bacterial Proteins/metabolism; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Enzyme Inhibitors/pharmacology; Gram-Positive Bacteria/drug effects; Guanidines/pharmacology; Phosphorylation; Protein Kinases/metabolism; Signal Transduction/drug effects; Trityl Compounds/pharmacology |
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